Guanylyl Cyclase Receptors Mediate Cardiopulmonary Vagal Reflex Actions of ANP

Abstract

Abstract-Atrial natriuretic peptide (ANP) potentiates vagal cardiopulmonary reflexes due to chemosensory (BezoldJarisch [B-J] reflex) or mechanosensory (ramp baroreflex) activation. The ANP receptor mediating these actions is unknown. We examined the role of particulate guanylyl-cyclase (pGC) receptors in ANP-induced enhancement of cardiopulmonary vagal reflexes. Cardiopulmonary baroreceptor reflex function was assessed by bradycardic responses to ramp blood pressure rises after rapid intravenous methoxamine (100 g/kg bolus dose). The B-J reflex was evoked by 3 intravenous doses of serotonin (1 to 10 g/kg). In conscious, chronically instrumented rats (nϭ9), these tests were performed on each animal during randomized infusions of rat ANP (150 ng/kg per minute IV), saline (270 L/h IV), the pGC receptor antagonist HS-142-1 (3 mg/kg IV), or combined HS-142-1ϩANP treatment. 4,5 There are 3 known natriuretic peptide receptor subtypes: A (NP A ), B (NP B ), and C (NP C ). 8 Most of the well-known biological actions, such as vasodilation and natriuresis, of the natriuretic peptides occur subsequent to stimulating the production of the second-messenger cyclic guanosine 3Ј 5Ј-monophosphate (cGMP), through particulate guanylylcyclase (pGC)-coupled receptors (the NP A and NP B receptors). The NP C receptor fulfills the role of a clearance receptor for the 3 natriuretic peptides. 9 In addition, while not having guanylylcyclase activity, this receptor has been reported to influence 3 signal-transducing systems: phospholipase C, adenylyl cyclase, and calcium channels. 9 The NP C receptor is proposed to be a physiological regulator of activities such as adrenergic transmission, renin and progesterone secretion, and platelet aggregation. 9 Although there is a growing body of literature linking natriuretic peptide receptors to the more widely known cardiovascular and renal actions of ANP, BNP, and CNP, 10 -15 the nature of the natriuretic peptide receptors involved in the HR reflex activities of these hormones has not been studied or reported in the literature. Since BNP and CNP share with ANP the ability to enhance reflex bradycardic responses, 4,5 a common receptor may mediate these effects. In the present studies, the contribution from the guanylyl cyclase receptors to the cardiopulmonary vagal baroreflex and chemoreflex (Bezold-Jarisch [B-J]) actions of ANP was investigated. HS-142-1 was used to selectively antagonize the NP A ϩNP B guanylyl cyclase-coupled (pGC) receptors. 16 HS-142-1 is a polysaccharide microbial product isolated from the culture broth of Aureobasidium species. 16 HS-142-1 blocks the vasodilator and renal effects of exogenously administered ANP and BNP and also reverses the changes resulting from augmented endogenous production of ANP and BNP. 10,17,18 Although HS-142-1 can exclude a role for the non-guanylyl cyclase receptor NP C , 16 this compound does not distinguish between subclasses of the pGC natriuretic peptide receptors.

Restorative Effect of Atrial Natriuretic Peptide or Chronic Neutral Endopeptidase Inhibition on Blunted Cardiopulmonary Vagal Reflexes in Aged Rats

“…This does not, however, rule out the possibility that old rats have some modest deficit in the basal level of natriuretic peptide signaling, which we have shown to be necessary for the full expression of the BJR. 19 Many other mechanisms could underlie the reduced reflex responsiveness of older rats, however, and the issue awaits direct study.…”

“…11,12,18,19 Briefly, (1) ramp baroreflex responses were assessed after rapid MAP increases of approximately 50 mm Hg evoked by methoxamine (100 g/kg intravenously; Sigma Chemical) aiming for a similar rate of MAP rise across all animals (approximately 20 mm Hg/s). Linear regression analysis was applied to the progressive HR responses to MAP changes.…”

“…This does not, however, rule out the possibility that old rats have some modest deficit in the basal level of natriuretic peptide signaling, which we have shown to be necessary for the full expression of the BJR. 19 Many other mechanisms could underlie the reduced reflex responsiveness of older rats, however, and the issue awaits direct study.The finding that endogenous ANP levels did not rise after 1 week of Candoxatrilat treatment is not uncommon. Other studies have shown that with chronic NEP inhibitor treatment, ANP levels re-establish at a steady-state level where release falls, compensating for the reduced clearance.…”

Effect of systemic B-type natriuretic peptide on cardiac vagal motoneuron activity

“…The action of BNP, as well as ANP and, to a lesser extent, CNP to enhance the von Bezold-Jarisch reflex bradycardia, is well established (22)(23)(24)(25): this action is mediated by particulate GC receptors since it is blocked by the pGC-receptor antagonist HS-142-1 (25). The site of this action of BNP and the other natriuretic peptides has been inferred to be on cardiac afferents.…”

“…This action has been shown in several species and may be produced by all three natriuretic peptides, although BNP is the most potent (23,27). This action is mediated by particulate guanylate cyclase (pGC) receptors (25), but their location is as yet uncertain. On the one hand, experiments on rats and sheep have found that BNP, in a dose that enhanced the von BezoldJarisch and "ramp" (cardiac) baroreflex, did not alter the bradycardic response to arterial baroreceptor loading [as assessed by the steady-state baroreceptor reflex (26,27)].…”